The development strategy for an effective tetravalent dengue vaccine has consisted of the clinical evaluation of monovalent vaccine candidates for each of the four serotypes with the goal of selecting suitable candidates for inclusion in a tetravalent formulation. Optimal admixtures (TV003 and TV005: DEN1del30, DEN2/4del30, DEN3del30/31, DEN4del30) have been selected and induce an unprecedented level of neutralizing antibody in sero-naive subjects that is both balanced among the serotypes and sufficient to provide sterile immunity against a second dose administered at six months. Following a single dose of TV005, the frequency of seroconversion in vaccinees to the individual serotypes 1 - 4 reached a remarkable 92%, 97%, 97%, and 97%, respectively, with 90% of vaccinees achieving a tetravalent antibody response. These data initially suggested that a single dose of vaccine may be sufficiently immunogenic and this has been demonstrated using challenge with a safety-tested DENV-2 challenge strain. This points to a significant advantage of the LID vaccine compared to other live attenuated DENV vaccines which require two or three doses to achieve a similar result. The selection of an optimal tetravalent admixture has enabled the further development of the vaccine by several manufacturers located in Brazil, India, Vietnam, and the United States. Through on-going technological and scientific support, these licensees are making significant progress in the development of the vaccine and a Phase III is underway in Brazil. Through an Interagency Agreement initiated with the Walter Reed Army Institute of Research, a Phase II study has been designed to evaluate the tetravalent vaccine in subjects of decreasing age in Bangkok, Thailand. In addition, an NIAID-sponsored Phase II trial is underway in subjects of decreasing age in Dhaka, Bangladesh. At LID, several clinical evaluations are ongoing: Safety and immunogenicity of TV005 in older adults (age 50 70 years), Safety and immunogenicity of a prime-boost vaccination regimen consisting of a TV005 prime vaccination followed by a dengue subunit boost (Merck), and TV005 vaccination followed by challenge with DENV-3. We have also enrolled two clinical studies to investigate the immune response to DENV. In the first study, subjects received a trivalent preparation of vaccine viruses (lacking DENV-2) and were then challenged with DENV-2 to evaluate cross-protection from DENV-1, -3, and -4. In the second study, we sought to model natural sequential infections by administering a DENV-1 vaccine followed 9 months later by challenge with DENV-2. From this study we are evaluating the repertoire of both cross-reactive and enhancing antibodies. The development of effective vaccination strategies against dengue virus infection and clinically significant disease remains a task of high global public health value and significance, while also being a challenge of considerable complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes and enhancement of subsequent dengue disease in young children, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results have challenged the hypothesis that seroconversion is the only reliable correlate of protection. We have shown that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. We are also currently investigating the CD4(+) T cell response. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV.